High plasma cholesterol and related lipids are known to be one of the factors that predispose an individual to atherosclerosis and thus to myocardial infarction. Diabetes mellitus, which eventually impairs the function of kidneys, eyes, nervous and vascular systems, is quite often associated with lipid disorders. Both hyperlipidemia and diabetes mellitus require long term management and pose problems in choice of pharmacotherapeutic interventions when these conditions manifest together. Though a number of drugs are known separately to treat these conditions, there are a number of side effects associated with them which limit their long term use.
The most important hypolipidemic drugs available today belong to the statin and fibrate classes [McCarthy, P. A., Med. Res. Rev., 13, 139-59 (1993)] whereas hypoglycemic drugs fall into the category of sulphonylureas, biguanidines and amidines [Wolff, M. E. (Ed), Burger's Medicinal Chemistry Part II, 1045 (1981), John Wiley & Sons, New York]. However, these therapeutic agents are not free of side effects-statins (HMG-CoA reductase inhibitors) the most widely used drugs today which hitherto were thought to be very safe drugs, have exhibited side effects following long term therapy [Carrier, M. et al.; Ann. Thorac. Surg., 57, 353-6 (1994)]. The adverse effects which have become the source of concern, are increases in hepatic transaminases and myopathies [Witztum, J. L., In Goodman & Gilman's The Pharmacological Basis of Therapeutics, eds. Hardman, J. et al. 9th edition, McGraw Hill, New York pp. 875-98, Fukami, M. et al; Res. Exp. Med., 193, 263-73 (1993); Appelkvist, E. et al.; Clin. Invest., 71 (suppl 8), 597-102 (1993), Wills, R. A. et al.; Proc. Natl. Acad. Sci. (US), 87, 8928-30 (1990)] and carcinogenesis, especially breast cancer in subjects undergoing treatment with pravastatin [Braunwald, E.; Scrip, 2117, 33 (1996)); Ciaravino, V. et al.; Mutat. Res.; 353, 95-107 (1995)]. The incidence of myopathy associated with rhabdomyolysis and renal failure is increased subsequent to such treatment [East, C. et al.; N. Engl. J. Med., 318, 47-48 (1998); Pierce L. R. et al.; J. Am.Med. Assoc., 265, 71-75 (1990)]. Also, these HMG-CoA inhibitors block mevalonate production which occurs at an early stage in cholesterol synthetic pathway. Mevalonate is a common precursor for all isoprenoids such as ubiquinones (Co-enzyme Q-10), the dolichols, isopentenyl t-RNA etc. Therefore, long term blockade of mevalonate synthesis leads to Q-10 deficiency. Serum Co-enzyme Q-10 is important for cardiac function [Laaksonen, R. et al., Eur. J. Clin. Pharmacol. 46,313-7 (1994); Bargossi, A. M. et al; Int.J. Clin. Lab. Res., 24, 171-6 (1994)]. The most common side-effects of fibrates and particularly clofibrate therapy are gastrointestinal upsets including nausea, vomiting, diarrhoea, dyspepsia, flatulence and abdominal discomfort [Oliver, M. F. et al.; Br. Heart J., 40,1069-1118 (1978)]. Elevated creatine phosphokinase concentration during clofibrate therapy may be associated with a syndrome of muscle pain and weakness. Large-scale long-term studies have demonstrated an increased incidence of cholecystitis, gallstones and sometimes pancreatitis in patients receiving clofibrate and some studies have indicated cardiovascular disorders [The coronary Drug Project Research Group; N. Engl. J. Med., 296, 1185-90 (1977)]. The unexpected finding of an increased mortality rate in patients taking clofibrate in the WHO study produced serious concern over the long-term safety of clofibrate and ultimately led to its withdrawal in many countries [Oliver, M. F. et al.; Lancet, ii, 600-604 (1984)].
The adverse effects of biguanidine antidiabetic agents include gastro-intestinal disturbances like diarrhoea and lactic acidosis [Paterson, K. R. et al.; Adverse Drug React Acute Poisoning Rev., 3, 173-82 (1984)]. With sulphonylureas the commonly associated adverse effects are hypoglycemia, gastrointestinal disturbances, hypersensitivity and vascular complications [Paice, B. J. et al., Adverse Drug React. Acute Poisoning, 4, 23-26 (1985)]. As diabetes and hyperlipidemia are quite commonly manifesting together, it would be of great clinical benefit if the same compound could have both these activities together because the available drugs are not free of toxic effects and neither data regarding toxic manifestations are available when drugs for two clinical conditions are mixed together.
Two approaches currently being pursued in search of drugs with hypolipidemic and hypoglycemic activities together. The first approach emerged during detailed study of antihypertensive action of adrenergic receptor modulators. The study revealed that a,-adrenergic blockers (particularly Doxazosin and Prazosin) [Lithell, H. O.; J. Hypertens, 15 (Suppl 1), S 39-42 (1997); Poliare, T. et al.; Diabetologia, 31, 415-420 (1988); Anderson, P. E. et al.; Am. J. Hypertens, 9, 323-333 (1996)] and β3-adrenergic agonist (BTA-243, BRL-37344, CGP 12177, CL 316243 [Arch, J. R. S. et al.; Med. Res. Rev., 13, 663-729 (1993); Largis, E. E. et al.; Drug Dev. Res., 32, 69-76 (1994)] also affect plasma lipoprotein metabolism and increase insulin sensitivity. As a result such antihypertensive drugs exhibit lipid lowering and hypoglycemic actions together. α1-adrenergic receptor blockers, however have the inherent limitations of causing orthostatic hypotension and syncope [Matyus, P.; Med. Res. Rev., 17(6), 523-35 (1977)]. The essential requirement of β3-agonist for antiobesity and antidiabetic actions is the need for high selectivity for β3-adrenoceptor. Any substantial β1- or β2-agonism would likely cause increased heart rate and muscle tremor respectively which are unacceptable in a drug which could be administered on long term basis [Connacher, A. A. et al.; Brit. Med. J., 296,1217-20 (1988); Mitchell, T. H. et al; Int. J. Obesity., 13(6), 757-66 (1989)]. The second line of approach for dual activity came into light during the study of anti-oxidant property of drugs. There have been many reports describing relationships between peroxidation and diseases such as diabetes mellitus, atherosclerosis and myocardial ischemia in terms of radical oxidation. Troglitazone, an antioxidant drug has been developed as an oral hypoglycemic agent which enhances the action of insulin in peripheral tissues and liver besides its hypolipidemic effects. However, troglitazone is also not free of major side effect causing liver damage. The drug, troglitazone, has been implicated in 35 cases of liver disease leading to one transplant and one death [Warner-Lambert; Chem. & Ind., No. 22, 897 (1977)]. Thus to the best of our knowledge no class of compound is yet available which has both effects together as the main action and have a fair safety margin.
We, in early eighties started our work for search of such compounds which have effect on endogenous transportation of lipids and glucose rather than interfering with exogenous transportation. Our research was mainly based on secondary metabolic actions of progesterone.
Progesterone, apart from its classical hormonal action on the reproductive system, is known to modulate lipid, carbohydrate, insulin and protein metabolism. The rise in the level of progesterone in the first trimester of pregnancy causes hyperphagia, pancreatic islet hypertrophy, hyperinsulinemia and body fat and glycogen deposition, when the metabolic demands of the fetus are very low. However, in the latter half of pregnancy, although the progesterone levels are still high, the carbohydrate, lipid and protein reservoirs shift into circulation to meet the needs of the growing fetus. [Kalkhoff, R. K.; Am. J. Obstet. Gynecol., 142, 735-38 (1982)].
Progesterone thus, having actions both on the reproductive and metabolic systems, seemed to offer the possibility of dissociating these two biological activities by structural modifications. The experience of the development of second generation progestins supported this contention. The first generation progestins such as levonorgestrel exhibited undesirable pharmacologic effects like alteration in carbohydrate and lipoprotein metabolism, weight gain and hypertension, which was shown to be related to their intrinsic androgenic/anabolic activity and ability to bind with androgen receptors. The androgenic affinity has been attributed to C-17 hydroxy functionality which makes these molecules resemble androgens. In recently discovered second generation progestins such as gestodene and 3-keto-desogestrel, an additional olefinic bond either in C- or D-ring brought a dramatic decrease in their affinity to androgen receptors (Table 1). As a result these compounds have a very high order of progestational effect with practically no androgenic activity and did not cause hyperlipidemia [London, R. S.; Obstetrical & Gynocological Survey, 47, 777-81 (1992)].
TABLE 1Relative Binding Affinity of Contraceptive Progestinsfor Progesterone and Androgen receptorsProgestinAndrogenReceptorReceptorSelectivityBindingBindingIndex*AffinityAffinity(A/P ratio)Progesterone1.000.00593Levonorgestrel5.410.220113-Keto-desogestrel8.60.12033Gestodene9.210.15428*The higher the selectivity index, the greater the separation between the dose needed to achieve the desired progestational effect and the dose associated with the undesired androgenic effect [Collins, D. C.; Am. J. Obstet. Gynecol. 170, 1508-13(1994)]. 